The carboxylic ionophores are potent coronary vasodilatory, inotropic and exocytosis promoting agents whose pharmacological activity arises from their ability to catalyze cation transport across biological membranes. Their unique cardiovascular effects have therapeutic potential, however, their large scale entry into man's food supply through their use as livestock feed additives is also a serious health concern. The catalytic transport cycle of ionophores involves the reversible formation of a lipophilic ionophore-ion inclusion complex in which the water molecules constituting the primary solvation sphere of an ion have been replaced by the liganding heteroatoms on the ionophore backbone. The complexation steps of the transport cycle occur in the polar head group regions of the membrane phospholipid bilayer. Model membranes of differing phospholipid head group composition show differential affinity toward a given ionophore as well as differential cation transport efficiencies for each equivalent of ionophore bound to the membrane. Phospholipid-ionophore interactions in free solution and in small unilamellar vesicles will be monitored by nuclear magnetic resonance, circular dichroism and fluorescence spectroscopy to determine the mechanism by which ionophores interact with biomembranes and the effect such interactions have upon the ability of the ionophore to select and complex cations. Particular emphasis will be placed on determining; 1) which functionalities of the ionophore are involved in the membrane binding; 2) the pre-complexation conformation of the membrane-incorporated ionophore 3) the orientation of the ionophore on the surface of the membrane; 4) the effects of membrane binding on the ion-recognition and ion binding reactions of the ionophore. Mechanistic information derived from this study will provide guidelines for the attenuation of membrane permeability by the synthesis of appropriately designed ionophores, the membrane binding characteristics and cation selectivity of which are targeted for specific membrane systems of specific phospholipid composition. Ultimately, this will enable us to select ionophores with optimal properties for promoting a desired biological or pharmacological effect within complex membrane systems such as an intact animal.